Lysosome-targeting chimeras (LYTACs) are a promising therapeutic modality to drive the degradation of extracellular proteins. However, early versions of LYTAC contain synthetic glycopeptides that cannot be genetically encoded. Here, we present our designs for a fully genetically encodable LYTAC (GELYTAC), making our tool compatible with integration into therapeutic cells for targeted delivery at diseased sites. To achieve this, we replaced the glycopeptide portion of LYTACs with the protein insulin-like growth factor 2 (IGF2). After showing initial efficacy with wild-type IGF2, we increased the potency of GELYTAC using directed evolution. Subsequently, we demonstrated that our engineered GELYTAC construct not only secretes from HEK293T cells but also from human primary T-cells to drive the uptake of various targets into receiver cells. Immune cells engineered to secrete GELYTAC thus represent a promising avenue for spatially selective targeted protein degradation.
Competing Interests: Competing interests statement:C.R.B. is a co-founder and scientific advisory board member of Lycia Therapeutics, Palleon Pharmaceuticals, Enable Bioscience, Redwood Biosciences (a subsidiary of Catalent), OliLux Bio, InterVenn Bio, GanNA Bio, Firefly Bio, Neuravid, and Valora Therapeutics. S.A.Y.-H. is a consultant for Quince Therapeutics. L.L. is a cofounder of, consults for, and holds equity in CARGO Therapeutics. E.S. is a consultant for Lepton Pharmaceuticals and Galaria, and holds equity in Lyell Immunopharma. C.L.M. is a cofounder of Lyell Immunopharma, CARGO Therapeutics, and Link Cell Therapies, which are developing CAR-based therapies, and consults for CARGO, Link Immatics, Ensoma and Red Tree Capital. A.Y.T. is a scientific advisor to Third Rock Ventures and Nereid Therapeutics. The remaining authors declare no competing interest. C.R.B. owns founders shares of Lycia Therapeutics, which is developing medicines based on targeted extracellular protein degradation.